Influence of chronic nitric oxide inhibition of coronary blood flow regulation: a study of the role of endogenous adenosine in anesthetized, open-chested dogs.

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The effect of chronic inhibition of endothelium-derived nitric oxide (NO) synthesis on the regulation of coronary blood flow (CBF) is yet to be elucidated. A chronic canine model of inhibited NO synthesis was created and the role of adenosine in the regulation of coronary blood flow in this model was examined. Dogs were fed a diet supplemented with 40 mg/kg per day N(G)-nitro-L-arginine methyl ester (L-NAME group, n=8) or a regular diet without L-NAME supplementation (control group, n=8) for 4 weeks. The experiments were performed in an anesthetized, open-chest state and the results were compared in the L-NAME and control groups. Chronic L-NAME treatment significantly increased arterial pressure. Neither basal CBF in the left anterior descending artery nor heart rate differed between the L-NAME and control groups. In the L-NAME group, the response of CBF to intracoronary acetylcholine and adenosine was blunted, but that to glyceryl trinitrate was not. In addition, myocardial reactive hyperemia following 20 sec coronary occlusion was blunted in the L-NAME group. During atrial pacing at a rate 60 beats/min faster than the sinus rate, CBF increased to a similar degree in the L-NAME and control groups, and systolic wall thickening (SWT) changed similarly in both groups. Intracoronary 8-phenyltheophylline (8-PT), an adenosine receptor blocker, decreased basal CBF in the L-NAME group but not in the control group. In the L-NAME group, pacing-induced increase in CBF was abolished and SWT deteriorated after 8-PT administration. Basal myocardial adenosine release was significantly increased in the L-NAME group compared with the control group. It is concluded that in anesthetized, open-chest dogs with chronic inhibition of NO synthesis, adenosine may play a compensatory role in the regulation of coronary blood flow, as concomitant blockade of adenosine causes deterioration of coronary circulation and cardiac function.